Down syndrome (DS) is a complex genetic disorder caused by a third copy of chromosome 21 resulting in triplication of −300 genes. It is the most common source of congenital anomalies with a prevalence of 1 per 733 live births in the US, resulting in the birth each year of 5,000 affected infants. Among several abnormalities occurring with DS, intellectual deficiencies that affect the quality of life for both children and adults is a primary concern. Understanding the neurobiological basis of failed cognition in DS is, thus, a high priority with the hope that deciphering pathogenesis will lead to effective therapies.
Failed learning and memory is essentially universal in people with DS. We have pursued a strategy that emphasizes the initial documentation of phenotypes followed by discovery of underlying gene dose effects and molecular and cellular mechanisms. The hippocampus (HC) is markedly affected in DS. This brain region is essential for registering events with respect to time and space. By modulating contextual discrimination, in which spatial information is integrated with other salient features of the environment, the HC mediates appropriate responses to dynamic changes in milieu. Among the many deficits present in children with DS, these individuals show severe defects in contextual tasks mediated by hippocampus. This phenotype is both robust and significant compromising the ability to carry out tasks of daily life. Interestingly, cued recall, in which memory is elicited by certain sensory cues is spared in DS; these tasks are modulated by amygdala and, unlike HC, this region shows no change in structure in young people with DS.
Individuals with DS may have some or all of the following physical characteristics: oblique eye fissures with epicanthic skin folds on the inner corner of the eyes, muscle hypotonia (poor muscle tone), a flat nasal bridge, a single palmar fold, a protruding tongue (due to small oral cavity, and an enlarged tongue near the tonsils), a short neck, white spots on the iris known as brushfield spots, excessive joint laxity including atlanto-axial instability, congenital heart defects, excessive space between large toe and second toe, a single flexion furrow of the fifth finger, and a higher number of ulnar loop dermatoglyphs. Most individuals with DS have mental retardation in the mild (IQ 50-70) to moderate (IQ 35-50) range, with individuals having mosaic DS typically 10-30 points higher. In addition, individuals with DS can have serious abnormalities affecting other body systems.
Since the majority of individuals with DS fall into the mild to moderate range of cognitive impairment, it has been estimated that even a small, perhaps, 10-20% improvement in cognitive functions could provide a significant number of these individuals with the ability to live independently rather than dependently.
Almost all individuals with DS will show Alzheimer's disease (AD) brain pathology after the age of 40. Furthermore, in a number of these cases dementia is exhibited.
While efforts have been made to improve cognitive ability in individuals having DS using vitamin E, studies have demonstrated that high doses of vitamin E may pose serious health risks. Furthermore, drugs with ability to increase the levels of brain acetylcholine (e.g. Aricept) and approved for the use in people with AD, have been used in people with DS and shown moderate improvement in cognition.
Parkinson's Disease (PD) is a degenerative disorder of the central nervous system that often impairs the motor skills, speech and other functions of afflicted individuals. While many forms of PD are idiopathic, i.e., no known cause, so-called secondary PD cases may arise from toxicity due to drugs, head trauma or other disorders. PD also causes neuropsychiatric disturbances, which include mainly cognition, mood and behavior problems.
It is known that symptoms of Parkinson's disease result from the greatly reduced activity of dopaminergic cells in the pars compacta region of the substantia nigra. This disruption of dopamine pathways is considered to be a likely explanation of much of the neuropsychiatric pathology associated with PD. Generally, in PD, neurons normally producing dopamine fail to function properly. The motor symptoms may include trembling of the hands, arms, legs and trunk; stiffness of the arms, legs and trunk; slowness of movement; and poor balance and coordination. Most commonly, PD commences at the age of about 60 years, but can begin at an earlier age. PD is more common in men than women. There is presently no known cure for PD.
Thus, a need exists for a method of treating individuals with DS and/or AD and/or PD to improve cognitive and/or motor ability in an effective manner without posing serious health risks.